Histamine and antihistamines

Histamine and
antihistamines
F1 Pongsawat Rodsaward

Outline
• Introduction
• Histamine
• Histamine
• Histamine receptor
• Histamine in immune response regulation
• Antihistamine
• Structure and Classification
• Pharmacokinetics and Pharmacodynamics
• Clinical uses
• Adverse reactions

Introduction
J Allergy Clin Immunol . 2011 Dec;128(6):1139-1150.e4.

Histamine (2-[4-imodazole]-ethylamine)
•is produced by various cells
•mast cells, basophils, lymphocytes
•gastric mucosa parietal cells
•central nervous system neuron
•is synthesized by decarboxylation of
histidine by l-histidine decarboxylase
(HDC), which depends on the cofactor
pyridoxal-5′- phosphate
+ pyridoxal-5′- phosphate (cofactor)
Middleton's Allergy: Principles and Practice, Ninth Edition

Histamine
•HDC gene
• found on chromosome 2 in mice and chromosome 15 in humans
• HDC gene expression is controlled by lineage-specific transcription factors.
• Regulation of HDC gene
• In hematopoietic cells - unknown
• nuclear factor E2 (NF-E2) appears to be involved indirectly in this mechanism.
• In basophils and mast cells
• results from the state of CpG methylation in the promoter region

Histamine
J Biol Chem. 1998 Nov 20;273(47):31607-14

•HDC activity is modulated by
• Cytokines -IL-1, IL-3, IL-12, IL-18, GM-CSF, M-CSF, TNF-α (in vitro)
• Calcium ionophore (in vitro)
• LPS stimulation, infection, inflammation, and graft rejection (in vivo)
Histamine

Histamine

Platelet-Activating Factor (PAF)
•Lipid inflammatory mediator
•Released from many immune cells, including eosinophils, MCs,
neutrophils, basophils, and epithelial cells
•Triggering degranulation, chemotaxis, and adhesion of immune cells, such
as eosinophils and MCs
•A post hoc analysis in a Japanese study showed that rupatadine, an H1
antihistamine with a PAF antagonist improved total pruritus score in
patients with AD.
Int J Mol Sci. 2021 Jul 5;22(13):7227.

• More than 97% of histamine is metabolized in two
major pathways before excretion.
• Histamine N-methyltransferase metabolizes most of
the histamine to N-methylhistamine.
• which is further metabolized to the primary
urinary metabolite N-methyl-imidazole acetic
acid by monoamine oxidase.
• Diamine oxidase metabolizes 15% to 30% of
histamine to imidazole acetic acid.
primary urinary metabolite
Histamine
15% to 30%

Histamine receptor
•Four subtypes of HR have been described: HR1, HR2, HR3, and HR4, or
H1R to H4R
•G protein–coupled receptor (GPCR) family

Comparison of different histamine receptors
Characteristic HR1 HR2 HR3 HR4
Distribution Smooth muscle,
endothelial cells,
CNS
Gastric parietal
cells, cardiac
muscle, mast cells,
CNS
CNS: pre- and
postsynaptic
Cells of
hematopoietic
origin
Best characterized
function
Acute
allergic
reactions
Gastric
acid
secretion
Neurotransmitter
modulation
Immunomodulator
G-protein
coupling
Gαq Gαs Gαi/o Gαi/o
Major signaling
pathway
Increases
in Ca2+
Increases
in cAMP
Inhibition of
cAMP
Increases
in Ca2+
Adapted from Chapter 39: Histamine, Bradykinin, and Their Antagonists, Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13e
Adapted from Nat Rev Drug Discov. 2008 Jan;7(1):41-53.

Histamine receptor 1
•Expression
• CNS neurons, smooth muscle cells (vascular, respiratory, GI), CVS, neutrophils,
eosinophils, monocytes, macrophages, DCs, T and B cells, endothelial cells,
epithelial cells

•Activation of HR1 results
• Airway smooth muscle contraction
à bronchoconstriction
• Synthesis of prostacyclin and platelet-
activating factor, release of von
Willebrand factor, and in NO release.
à increases vascular permeability,
platelet aggregation
Nat Rev Drug Discov. 2008 Jan;7(1):41-53.

• Expression
• Gastric parietal cells, smooth muscle, CNS, CVS,
neutrophils, eosinophils, monocytes, macrophages, DCs,
T and B cells, endothelial cells, epithelial cells
• Activation of HR2 results
• induce airway mucus production, vascular permeability,
and secretion of gastric acid
• Increase heart rate and cardiac output
• negatively regulate the release of histamine on basophils
and mast cells.
• Inhibit antibody synthesis, T cell proliferation, cell-
mediated cytolysis, and cytokine production

• Expression
• CNS (pre- and postsynaptic), CVS, lungs,
monocytes, eosinophils, endothelial cells
• HR3 is involved in cognition, sleep-wake cycle,
homeostatic regulation, and inflammation
• Suppressed norepinephrine release at
presynaptic nerve endings and stimulated nasal
sub-mucosal gland secretion

•Expression
• Neutrophils, eosinophils, monocytes, DCs, Langerhans cells, T cells, basophils,
mast cells, fibroblasts, bone marrow, endocrine cells, CNS

• Stimulation of mast cells
• increases chemotaxis of mast cells thus encouraging their accumulation at the site of an
allergic response
• upregulates the expression of FcεRI on mast cells, thereby priming them for allergen-induced
activation
• mobilizes intracellular calcium to either prime mast cells for activation
• Enhance the migration of eosinophils
• induces IL-31 production à pruritus in atopic dermatitis
• Involved in T cell differentiation and dendritic cell activation and its immunomodulatory
function
Int J Mol Sci. 2021 Jul 5;22(13):7227.

Front Immunol. 2018 Aug 13;9:1873.

Pruritus
• Itch specific pathway
• Itch-sensing C-fibres in the
periphery and histamine-
specific spinal neurons
projecting into the thalamus of
the brain
• Dorsal root ganglion neurons
have been shown to express
H1 receptors and exhibit H1
receptor-dependent firing in
response to histamine.
Nat Rev Drug Discov. 2008 Jan;7(1):41-53

II.III Histamine in immune
response regulation

Histamine in immune response regulation
•Antigen-Presenting Cells
•T Cells and Antibody Isotypes

Antigen-Presenting Cells
Immunology. 2018 May; 154(1): 3–20.

•Endogenous histamine is actively synthesized during cytokine-induced DC
differentiation, which acts in autocrine and paracrine fashion and modifies
DC markers.
•Immature and mature DCs express all four HR.
• Their levels of expression have not yet been compared.

•HR1 and HR3
• Monocyte à DC1
• positive stimulants to increase antigen presentation capacity and proinflammatory
cytokine production and Th1 priming activity
•HR2
• HR2 stimulation on monocytes stimulated with TLR–triggering bacterial products
• inhibits the production of proinflammatory IL-1 like activity, TNF-α, IL-12 and IL-18
• enhancing IL-10 production à suppress antigen presentation capacity
• downregulates CD14 expression on human monocytes (co-receptor along with the TLR4)

T Cells and Antibody Isotypes

II.I Structure and classification

Structure and Classification
• First -generation H1 antihistamines
• low H1-receptor selectivity
• inhibit transmission at muscarinic cholinergic receptors, α-adrenergic receptors, and 5-
hydroxytryptamine (5-HT, serotonin) receptors
• High lipophilicity
• Low molecular weight
• Positive electrostatic charge
• Second -generation H1 antihistamines
• highly specific for the H1 receptor
• have little or no affinity for muscarinic cholinergic, α-adrenergic, or serotonin receptors
enhances brain penetration

Structure and Classification

Chemical Class First Generation Second Generation
Alkylamines Brompheniramine, chlorpheniramine,
dexchlorpheniramine, dimethindene, pheniramine,
triprolidine
Acrivastine
Piperazines Buclizine, cyclizine, hydroxyzine, meclizine,
oxatomide
Cetirizine, levocetirizine
Piperidines Azatadine, cyproheptadine, diphenylpyraline,
ketotifen
Astemizole, bepotastine, bilastine, desloratadine,
ebastine, fexofenadine, levocabastine, loratadine,
mizolastine, rupatadine, terfenadine, alcaftadine
Ethanolamines Carbinoxamine, clemastine, dimenhydrinate,
diphenhydramine, doxylamine, phenyltoloxamine
Ethylenediamines Antazoline, pyrilamine, tripelennamine
Phenothiazines Methdilazine, promethazine
Other Doxepin Azelastine, emedastine, epinastine, olopatadine

Rupatadine
•non-sedating H1-antihistamine that also has with additional antagonist
effects on platelet-activating factor (PAF)
Drugs. 2007;67(3):457-74.

The agonist, histamine, has preferential affinity for the active state,
stabilizes the receptor in this conformation, and shifts the
equilibrium toward the active state.
The inactive state of histamine H1 receptor is in equilibrium with
the active state.
An H1 antihistamine (inverse agonist) has preferential affinity for
the inactive state, stabilizes the receptor in this conformation, and
shifts the equilibrium toward the inactive state.

II.II Pharmacokinetics and
Pharmacodynamics

Pharmacokinetics
•Absorption
•Distribution
•Metabolism
•Excretion

Pharmacokinetics
•The pharmacokinetics of the first -generation H1 antihistamines have not
been optimally investigated in healthy adults or in vulnerable patients, such
as children, elderly persons, patients with hepatic or renal dysfunction, or
in drug interaction studies

• Bioavailability is influenced by several types of drug transporters
• including ATP-binding cassette (ABC transporters) such as organic anion transport protein (OATP)
and P-glycoprotein expression on the luminal surfaces of intestinal endothelial cells.
• Co-administration with food (depending on meal)
• Loratadine AUC increased by more than 50%
• Rupatidine AUC increased by 26%
• Bilastine AUC decreased by 30%
• P-glycoprotein inducers such as grapefruit juice, rifampin
• potential to decrease fexofenadine absorption (24% lower AUC value)
• Fexofenadine is also an organic acid that binds to aluminum- and magnesium-containing
antacids
• administration within 15 minutes of ingestion of these agents should be avoided
Pharmacokinetics-Absorption

•First-generation H1 antihistamines
• cross the BBB and occupy greater than 50% to 70% of the H1 receptors located
on the presynaptic membranes of histaminergic neurons throughout the CNS
•Second-generation H1 antihistamines
• do not cross the BBB readily
• Fexofenadine and bilastine are a substrate of the P-glycoprotein efflux
transporter in the blood-brain barrier (BBB)
• prevents its penetration into the central nervous system
Pharmacokinetics-Distribution

Pharmacokinetics-Metabolism
•Metabolized in the hepatic CYP450 system
• First-generation H1 antihistamines
• Desloratadine
• Loratadine
• Rupatadine
Alternative CYP2D6 pathway

•Second-generation H1 antihistamines are excreted largely unchanged in
the urine and feces
Pharmacokinetics-Excretion

Pharmacokinetics-Metabolism, Excretion
Metabolism Excretion
Drug Liver Enzyme Renal Fecal
Cetirizine Minimal Oxidative O-
dealkylation
70% (approximately
50% unchanged)
10%
Levocetirizine <14% CYP3A4 Renal: 85.4%
(approximately 80%
unchanged)
12.9%
Loratadine Major CYP3A4 approximately 40%
as metabolites
approximately 40%
as metabolites
Desloratadine Major CYP2C8 40.6% primarily as
metabolites
46.5% as
metabolites
Fexofenadine 0.5% to 1.5% CYP3A4 11% 80%
Rupatadine Major CYP3A4 34.6% 60.9%
IBM Micromedex
Lexicomp Uptodate

Pharmacodynamics
•Onset of Action
•Peak Action
•Duration of Action
•Residual Action

Clinical uses

Allergic rhinitis
J Allergy Clin Immunol. 2020 Jan;145(1):70-80.e3.

Allergic conjunctivitis
• Oral second-generation antihistamines should be preferred over first-generation
antihistamines.
• In cases of dry eye, first-generation oral antihistamines are to be discontinued.
• No single agent in second-generation antihistamines has been conclusively found
to achieve superior overall response rates.
• Topical antihistamines are effective in the treatment of allergic conjunctivitis.
• The concomitant use of an eye drop and second-generation oral antihistamine
may be required to maximize the treatment of ocular allergic symptoms.
Ann Allergy Asthma Immunol. 2020 Feb;124(2):118-134.

Urticaria
Allergy. 2018 Jul;73(7):1393-1414.

•This has been verified in studies using up- to fourfold higher than
recommended doses of
• Bilastine
• Cetirizine
• Desloratadine
• Ebastine
• Fexofenadine
• Levocetirizine
• Rupatadine
Urticaria
Allergy. 2018 Jul;73(7):1393-1414.

ยาที%มีการศึกษาว่า เมื%อมีการเพิ%มขนาดยาที%
รับประทานได้ถึง ? เท่าจะเพิ%มประสิทธิภาพใน
การรักษาแต่ไม่เพิ%ม อุบัติการณ์ของอาการไม่พึง
ประสงค์จากยาได้แก่ยา
Levocetirizine
Desloratadine
Fexofenadine
Rupatadine
Urticaria
Clinical Practice Guideline 2557 แนวทางการดูแลรักษาโรคลมพิษ

Bilastine >12 yrs 20 mg OD >12 yrs 20 mg OD No dosage adjustment needed Information related to the use in pregnancy is
limited

2nd Generation Antihistamine Standard Dosage for Age
Cetirizine 6 months to <2 years : 2.5 mg OD
Levocetirizine 6 months to < 5years: 1.25 mg OD
Rupatadine 2 years to <12 years (10-25kg): 2.5 mg OD (oral solution)
Asthma Allergy. 2021 Mar 9;14:187-199.
Second generation H1 antihistamine

Drug Liver disease Kidney disease
CrCl<10 CrCl<30 CrCl<50 CrCl<80
Cetirizine 5 mg OD 5 mg AD 5 mg OD ✓ ✓
Levocetirizine ✓ ✕ 2.5 mg twice
weekly
2.5 mg AD 2.5 mg OD
Loratadine Caution 10 mg AD 10 mg AD ✓ ✓
Desloratadine Caution 5 mg AD 5 mg AD ✓ ✓
Fexofenadine ✓ 60 mg OD 60 mg q12-24hr ✓
Rupatadine ✕ ✕ ✕ ✓ ✓
Bilastine ✓ ✓ ✓ ✓ ✓

Drug Liver disease Kidney disease
Cetirizine > 6 m to < 6yr Avoid use Avoid use
> 6yr No adjustment No adjustment
Levocetirizine > 6 m to < 11yr ✓ Contraindicated
>12 yr ✓ Same as adult
Loratadine > 2 yr ✓ No adjustment
>12 yr ✓ Same as adult
Desloratadine >6 m No dosage adjustment provided No dosage adjustment provided
Fexofenadine >6 m to < 2 yr ✓ 15 mg OD
>2 yr to <12 yr ✓ 30 mg OD
>12 yr ✓ 60 mg OD
Rupatadine >2 yr to <12 yr Not recommended Not recommended
Bilastine >12 yr ✓ ✓

Adverse reaction
•Central Nervous System
•Cardiac Effects
•Anticholinergic Effects
•Other Potential Adverse Effects
•Overdose Toxicity and Fatality

Central Nervous System
•First-generation H1 antihistamines cross the BBB and interfere with
neurotransmission in the histaminergic system
• occupy greater than 50% to 70% of the H1 receptors located on the presynaptic
membranes of histaminergic neurons throughout the CNS especially in the
frontal cortex, temporal cortex, hippocampus, and pons
• decreased histaminergic neurotransmission and impaired CNS function on objective
testing, with or without associated sedation, drowsiness, fatigue, or somnolence

•Based on the degree of H1-receptor occupancy after single-dose
application, antihistamines can be classified
• sedating (more than 50%)
• less sedating (20% to 50%)
• nonsedating

•Antihistamine hangover
• the morning after, in patients who have CNS residual effects such as impairment
with or without sedation
•The adverse CNS effects of first-generation H1 antihistamines are
potentially exacerbated by concurrently ingested ethanol,
benzodiazepines, and other CNS-active chemicals
•Increase the latency to onset of rapid eye movement sleep and reduce the
duration of rapid eye movement sleep

Cardiac effect
•Blockade of cardiac ion currents, such as the rapid component of the
delayed outward rectifying potassium channel (IKr) or the rapid component
of the inward rectifying sodium channel (INa)
• Potentially prolong the QTc interval and lead to cardiac arrhythmias (1st
generation)

Anticholinergic Effects
• Many of the first-generation H1 antagonists tend to inhibit muscarinic cholinergic
responses and may be manifest during clinical use
• H1 antagonists also can be used to treat motion sickness, probably as a result of
their anticholinergic properties.
• Promethazine has perhaps the strongest muscarinic-blocking activity among
these agents and is the most effective H1 antagonist in combating motion
sickness.
• The second-generation H1 antagonists have no effect on muscarinic receptors
Chapter 39: Histamine, Bradykinin, and Their Antagonists, Randal A. Skidgel ©2021 McGraw Hill.

Other Potential Adverse Effects
•Blockade of serotonin receptor
• appetite stimulation and weight gain, especially with cyproheptadine and
ketotifen
•Blockade of α-adrenergic receptor
• peripheral vasodilation, orthostatic hypotension, and dizziness
•The second-generation H1 antagonists have no effect on serotonin and α-
adrenergic receptor

Overdose Toxicity and Fatality
• First-generation H1 antihistamines
• Infants and young children
• Paradoxic excitation with irritability, hyperalertness, hallucinations, and seizures typically
precedes drowsiness, confusion, delirium, coma, and respiratory depression.
• In patients of all ages
• Anticholinergic effects
• dryness of the mucous membranes, fever, flushed face, pupillary dilation, urinary retention, decreased
gastrointestinal motility, hypotension, and tachycardia
• Prolongation of QTc interval and ventricular arrhythmias
• Up to 30-fold overdoses of cetirizine, fexofenadine, and loratadine have not been
causally associated with serious adverse events or fatality

Drug Common adverse effects Serious adverse effects
Cetirizine Gastrointestinal: Xerostomia (5% )
Neurologic: Headache (Adult, less than 1%; Pediatric, 2% or greater ), Sedated,
Somnolence (2% or greater )
Other: Fatigue (6% )
Ophthalmic: Oculogyric crisis
Levocetirizine Gastrointestinal: Constipation (Infants, 7% ), Diarrhea (Infants, 13%; pediatrics,
4% ), Painful teething (Infants, 6.7% ), Vomiting (Pediatrics, 4% ), Xerostomia
(Adults and adolescents, 2% to 3% )
Otic: Otitis media (Pediatric, 3% )
Respiratory: Nasopharyngitis (Adults and adolescents, 4% to 6% ), Pharyngitis
(Adults and adolescents, 1% to 2% )
Other: Fever (Pediatric, 4% )
Renal: urinary retention
Loratadine Gastrointestinal: Xerostomia (3% )
Neurologic: Headache (12% ), Somnolence (8% )
Other: Fatigue (2% to 4% )
-
Desloratadine Gastrointestinal: Xerostomia (3% )
Musculoskeletal: Myalgia (2.1% )
Neurologic: Headache (14% ), Somnolence (2.1% to 9.1% )
Reproductive: Dysmenorrhea (2.1% )
Respiratory: Pharyngitis (3% to 4.5% )
Other: Fatigue (2.1% to 5% )
-
IBM Micromedex
Lexicomp Uptodate

M
Drug Common adverse effects Serious adverse effects
Fexofenadine Gastrointestinal: Stomachache (2.1% )
Musculoskeletal: Backache (2.1% to 2.5% )
Neurologic: Dizziness (2.1% ), Headache (4.8% to 10.3% ), Somnolence
Other: Fatigue, Pain in limb (2.1% )
-
Rupatadine Gastrointestinal: Gastroenteritis (>5% ), Odynophagia (>5% ), Sore throat
(>5%), Vomiting (5% ), Abdominal pain (2%), Xerostomia (2%)
Neurologic: Somnolence (9% ), Headache (6% ), hypersomnia (2%)
Reproductive: Dysmenorrhea (>5%)
Respiratory: Allergic conjunctivitis (>5% ), Allergic rhinitis (>5%), cough (>5%),
flu-like symptom (>5%), nasopharyngitis (>5%), rhinitis (>5%), tonsillitis (>5%)
Other: Fatigue >5%
Cardio: prolonged QT interval
(1%)
Bilastine Gastrointestinal: Upper abdominal pain (1%)
Neurologic: Dizziness (1% ), Headache (4% ), Somnolence (4%)
-
IBM Micromedex
Lexicomp Uptodate

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